Many smokers use cigarettes as a means to combat stress. Removal of nicotine, without addressing the underlying physiological changes associated with nicotine use, results in an unbalanced system that compels a return to smoking to alleviate the withdrawal symptoms. Some of the behavioral and addictive properties of nicotine appear related to its activation of the hypothalamic-pituitary-adrenal (HPA) axis, that is intimately involved in the stress response. Acute administration of nicotine has been shown to stimulate ACTH and corticosterone/cortisol secretion in both rodents and humans. Studies on chronic nicotine administration in animals suffer from methodological difficulties, but chronic nicotine was also found to activate the HPA axis, albeit to a lesser extent than acute nicotine. The stimulation of the HPA axis by nicotine may mediate some of the physiological and behavioral effects of nicotine. Our preliminary data support our hypothesis that chronic stress leads to an enhanced sensitivity to acute nicotine. Similarly, we expect that chronic nicotine (infused in a non-stressful manner) will result in enhanced sensitivity to an acute stress. Thus, we postulate that humans smoke more during stressful conditions to achieve an enhanced, pleasurable activation of the HPA axis. Furthermore, the drop in glucocorticoids following cessation of smoking in an individual under stress, will lead to a more dramatic glucocorticoid withdrawal, making smoking cessation less palatable than if the smoker was not in a stressful condition. This hypothesis goes against prevailing dogma, in which the smoker uses more cigarettes during stress to overcome the decreased HPA axis activity. Therefore, our study, especially if the preliminary data is supported by the proposed experiments, will change our understanding of the interaction of stress and chronic nicotine. This grant will provide provocative preliminary data for a future RO1 grant fully examining the relationship between the stress response and nicotine addiction. These experiments in mice, done using a nicotine infusion paradigm that is not stressful, should clarify the relationship between chronic stress and the nicotine-induced stimulation of the HPA axis. The use of agents which modify the stress response such as glucocorticoid synthesis inhibitors (ketoconazole, aminoglutethimide or metyrapone) or antagonists (RU-486), CRH antagonists, such as antalarmin, or agents which effect the metabolism of cortisol, such as carbenoxolone or licorice, may be helpful adjuncts in smoking cessation programs in humans.